Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma

Nat Cell Biol. 2024 Jun;26(6):1003-1018. doi: 10.1038/s41556-024-01428-5. Epub 2024 Jun 10.

Abstract

Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma* / drug therapy
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Isocitrate Dehydrogenase* / genetics
  • Isocitrate Dehydrogenase* / metabolism
  • Mice
  • Mutation
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Tumor Microenvironment*
  • Xenograft Model Antitumor Assays

Substances

  • Isocitrate Dehydrogenase
  • RNA-Binding Proteins
  • Antineoplastic Agents